Isoproterenol Disrupts Intestinal Barriers Activating Gut-Liver-Axis: Effects on Intestinal Mucus and Vascular Barrier as Entry Sites

Abstract

Background: The gut-liver-axis presents the pathophysiological hallmark for multiple liver diseases and has been proposed to be modulated during stress and shock. Access to the gut-liver-axis needs crossing of the mucus and gut-vascular barrier. The role of β-adrenoreceptor-activation for both barriers has not been defined and is characterized here. Methods: Splanchnic β-adrenergic stimulation was achieved by chronic intraperitoneal application of isoproterenol via alzetpump in vivo. The intestinal permeability and gut-vascular barrier function was assessed in ileal loop experiments. The extravasation of predefined sizes of fluorescence isothiocyanate (FITC)-dextran molecules in ileal microcirculation was evaluated by intravital confocal laser endomicroscopy in vivo. Mucus parameters thickness, goblet cell count and mucin-expression were assessed by stereomicroscopy, immunostaining and RNA-sequencing respectively. Ileal lamina propria (LP) as well as mesenteric lymph node mononuclear cells was assessed by FACS. Results: Healthy mice lack translocation of 4 kDa-FITC-dextran from the small intestine to the liver, whereas isoproterenol-treated mice demonstrate pathological translocation (PBT). Mucus layer is reduced in thickness with loss of goblet-cells and mucin-2-staining and-expression in isoproterenol-treated animals under standardized gnotobiotic conditions. Isoproterenol disrupts the gut vascular barrier displaying Ileal extravasation of large-sized 70-and 150 kDa-FITC-dextran. This pathological endothelial permeability and accessibility induced by isoproterenol associates with an augmented expression of plasmalemmalvesicle-associated-protein-1 in intestinal vessel. Ileal LP after isoproterenol treatment contains more CD11c+-dendritic cells (DC) with increased appearance of CCR7+ DC in mesenteric lymph nodes. Conclusions: Isoproterenol impairs the intestinal muco-epithelial and endothelial-vascular barrier promoting PBT to the liver. This barrier dysfunction on multiple levels potentially can contribute to liver injury induced by catecholamines during states of increased β-adrenergic drive.

Dietary Supplementation with Spray-Dried Porcine Plasma Attenuates Colon Inflammation in a Genetic Mouse Model of Inflammatory Bowel Disease

“…Our Mdr1a KO mice showed a reduction in the number of goblet cells in the colon, as well as in the expression of Muc2 and Tff3 , which would contribute to an increase in the epithelial permeability of the colon [ 28 ]. Indeed, it has been described that a reduction in goblet cells and Muc2 would be associated with an increase in pathogenic bacteria in the mucus layer and a greater penetration of these microorganisms into the mucosa [ 29 ]. SDP supplementation did not improve goblet cell abundance in KO mice but did attenuate the decrease in Muc2 expression and maintained Tff3 expression at similar levels to those of healthy animals.…”

To stress or not to stress: Brain-behavior-immune interaction may weaken or promote the immune response to SARS-CoV-2

“…In addition, the cholinergic system of the skin and mucous membranes seems to play a special role in the stability of the barrier, as chronic, long-term psychosocial stress can compromise the skin's barrier function by modulating nicotine receptors on epithelial cells ( Curtis et al, 2012 ). Psychosocial stress was also shown to disrupt the function of the intestinal barrier ( Barreau et al, 2007 ; Moussaoui et al, 2017 ) and in this context the agonists of the beta-adrenergic receptor and the neuropeptides corticotropin-releasing hormone (CRH) and substance P (SP) were found to enhance barrier permeability ( Keita et al, 2010 ; Sorribas et al, 2019 ), while mast cell stabilizers and neutralization of the neurotrophin nerve growth factor (NGF) were able to improve barrier function ( Barreau et al, 2007 ; Kritas et al, 2020 ).…”

The Programmed Death-1 Signaling Axis Modulates Inflammation and LV Structure/Function in a Stress-Induced Cardiomyopathy Model

“… 41 Although the reason(s) for the discrepancy between this and prior studies and the report by Liao et al 41 are not clear, they may relate, at least in part, to differences in the technique for injecting ISO IP, which can lead to transient hypotension 42 and increased gut permeability. 43 In our early studies with this model, we observed that mice that did not resume normal locomotor activity and developed a hunched posture and ruffled for 3-7 days after ISO injection also lost body weight and developed profound lymphopenia, and were distinctly different biologically from mice that recovered rapidly following ISO injection. With refinements in the ISO injection technique, we observed that the majority of ISO-injected animals recovered completely, consistent with what has been observed in patients with stress-induced cardiomyopathy.…”